12-oxygenated-4, 9(11)-pregnadiene-3, 20-dione



2,814,629 Patented N ov. v23, 1957 United States Patent OfificeIZ-OXYGENATED-4,9(11)-PREGNADIENE-3,20-

v DIONE 5 Josef Fried and Josef E. Herz, New Brunswick, N. J., as-

signors to Olin Mathieson Chemical Corporation, New York, N. Y., acorporation of Virginia No Drawing. Application July so, 1956, m

Serial No. 600,674 T 5 Claims. (Cl. 260397.3)

wherein R is hydrogen, R is a-hydroxy or a-acyloxy (particularly theacyloxy radical of a hydrocarbon carboxylic acid of less than ten carbonatoms, as exemplified by the lower fatty acids), and together R and R'is keto.

To prepare the steroids of this invention, ll-dehydroprogesterone istreated with a hydroxybrominating agent in the presence of water toyield A -pregnadiene-12aol-3,20-dione, which can then, if desired, beacylated in the usual manner to yield a 12u-acyloxy derivative oroxidized to A -pregnadiene-3,12,20-trione. Among the hydroxybrominatingagents utilizable in the process of this invention may be mentioned anN-bromamide of a lower alkanoic acid (e.'g., N-bromacetamide), an N-bromimide of a lower alkanedioic acid (e. g., N-bromosuccinimide), anddibromodimethylhydantoin. The reaction is optimally carried out in thepresence of a strong acid (e. g., perchloric acid or sulfuric acid). Thereaction can be conducted at any normal temperature (e. g., ambienttemperature) under normal pressure (e. g., ambient pressure).

The reaction results, inter alia, in the production of A-pregnadiene-12u-ol-3,20-dione, which can then be acylated in the usualmanner by treatment with an acyl halide or acid anhydride, such asacetic anhydride, propionic anhydride, or benzoyl chloride. Thisreaction is preferably carried out in an organic base such as pyridine.

The A -pregnadiene-12a-ol-3,20-dione can also be oxidized, as bytreatment with a hexavalent chromium compound (e. g., chromic acid), toA -pregnadiene- 3,12,20-trione.

The steroids of this invention are physiologically active compoundswhich possess progestational activity. Thus, these new steroids can beadministered instead of, and in the same manner as, progesterone in thetreatment of habitual abortions. The dosage for such administration is,of course, dependent on the relative activity of the steroid. Thus,where the steroid in question has approximately the same activity asprogesterone, the dosage of the former should be approximately equal tothe employed dosage of the latter.

The following examples are illustrative of the invention (alltemperatures being in centigrade):

EXAMPLE 1 A -pre'gnadie'ne-IZa 0l-3,20-di0ne To a solution of 900 mg. ofll-dehydroprogesterone in ml. of dioxane is added 54, ml. of 0.16 Nperchloric acid and 540 mg. of N-bromacetamide. After 20 min--utesatroom temperature, dilute sodium sulfite solution is added todestroy excess N-bromacetamideand ml. 7 of chloroform is added. Afterseparation of the layers,

the chloroform-dioxane phasefis washed with water, dilute sodiumbicarbonate and again with water and the solvents removed in vacuo at20. The residue crystallizes readily from acetone-hexane, yielding crude12u-bromo-11fl-hydroxyprogesterone. Concentration of the acetone-hexanemother liquor in vacuo yields A -pregnadiene-12u-ol- 3,20-dione, whichafter recrystallization from acetone, has the following properties: M.P. about 181-182; [a] +181 (c, 0.95 in chloroform);

Mia 239 mp (e=16,300);

&3?

2.92, 2.98, 5.92, 6.02 and 6.21 11..

Analysis.-Calcd. for H21H2s03 (328.44): C, 76.79; H, 8.59. Found: C,76.46; H, 8.49.

EXAMPLE 2 A -pregnadiene-l2a-0l-3,20-di0ne IZu-acetate A solution of 15mg. of A -pregnadiene-lZu-ol- 3,20-dione in 0.5 ml. of pyridine and 0.5ml. of acetic anhydride is allowed to stand at room temperature for 18hours. Evaporation of the reagents in vacuo leaves A-pregnadiene12ot-ol-3,20-dione 12a-acetate, which could not be inducedto crystallize. It has the following properties: [a] +322 (c, 1.7 inchloroform);

Achloroiorm max.

No OH bands, 5.80, 5.88, 6.01 and 6.19 ,u.

Similarly, by substituting propionic anhydride or benzoyl chloride forthe acetic anhydride in the procedure of Example 2, the 12a-propionateand 12a-benzoate, respectively, are formed.

EXAMPLE 3 A -pregnadiene-3,12,20-trione A solution of 15 mg. of A-pregnadiene-12a-ol- 3,20-dione in 2 ml. of acetone is oxidized with0.035 ml. of a solution of chromium trioxide (200 mg.)-sulfuric acid(320 mg.) in 1 ml. Water. The reaction is stopped by the addition of afew drops of alcohol and the mixture diluted with water and chloroform.The chloroform layer is washed with water, dilute bicarbonate and waterand the solvent removed in vacuo. The residue after crystallization fromacetone has the following properties: M. P. about 197-198; [a] |-168 (c,0.68 in chloroform);

mg; 239 my Analysis.Calcd. for CarHzeOz (326.42): C, 77.27; H, 7.31.Found: C, 77.22; H, 7.92.

The invention may be otherwise variously embodied within the scope ofthe appended claims.

whereinR is hydrogen, R is selected from the group consisting ofm-hydroxy and the a-acyloxy radical of a 15 hydrocarbon carboxylic acidof less than ten carbon atoms, and together R and R is oxygen.

2. A -pregnadiene-12a-o1-3,20-dione. 3. An ester of A-pregnadiene-12u-0l-3,20-di0ne and a hydrocarbon carboxylic acid of lessthan ten carbon atoms.

4. A -pregnadiene-12a-o1-3,20-di0ne IZa-acctatc. 5. A (1 )-prgnadiene-3,12,20-trione.

References Cited in the file of this patent UNITED STATES PATENTSReichstein Oct. Levin Feb Levin Oct.

Levin Dec Levin Dec

1. A STEROID OF THE GENERAL FORMULA